The role of IL-17 and IL-17-producing CD4^(+) T cells in acute graft-versus-host disease(GVHD)has been controversial in recent mouse and human studies.We carried out studies in a murine acute GVHD model of fully major...The role of IL-17 and IL-17-producing CD4^(+) T cells in acute graft-versus-host disease(GVHD)has been controversial in recent mouse and human studies.We carried out studies in a murine acute GVHD model of fully major histocompatibility complex-mismatched myeloablative bone marrow transplantation.We showed that donor wild-type CD4^(+) T cells exacerbated acute GVHD compared with IL-17−/−CD4^(+) T cells,while IL-17 reduced the severity of acute GVHD.The augmentation of acute GVHD by transferred donor IL-17-producing CD4^(+) T cells was associated with increased Th1 responses,while IL-17 decreased the percentages of Th1 cells in the GVHD target organs.Furthermore,IL-17 reduced the infiltration of macrophages into the GVHD tissues.In vitro study showed that IL-17 could downregulate Th1 responses,possibly through inhibiting IL-12 production by donor macrophages.Depletion of macrophages in vivo diminished the protective effect of IL-17.Our results demonstrated the differential roles of adoptively transferred donor IL-17-producing CD4^(+) T cells and IL-17 in the same acute GVHD model.展开更多
FTY720, an agonist for four of the five known sphingosine- 1-phosphate (SIP) receptors, has been reported to inhibit acute graft-versus-host disease (aGVHD). Because FTY720 functions through multiple SIP receptors...FTY720, an agonist for four of the five known sphingosine- 1-phosphate (SIP) receptors, has been reported to inhibit acute graft-versus-host disease (aGVHD). Because FTY720 functions through multiple SIP receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective SIP receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an SIPl-selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an SIPl-selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.展开更多
Dear Editor,Acute graft-versus-host disease(aGVHD)is the leading cause of transplantation-related mortality,and limits therapeutic benefits of allogeneic bone marrow transplantation(allo-BMT).New insight is needed int...Dear Editor,Acute graft-versus-host disease(aGVHD)is the leading cause of transplantation-related mortality,and limits therapeutic benefits of allogeneic bone marrow transplantation(allo-BMT).New insight is needed into the development of aGVHD.Most nutritional metabolites contribute to host health and immune homeostasis.展开更多
Interleukin 27(IL-27),a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28,is a pleiotropic cytokine with both pro-and anti-inflammatory properties.However,the precise role of IL-27 in acute graft...Interleukin 27(IL-27),a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28,is a pleiotropic cytokine with both pro-and anti-inflammatory properties.However,the precise role of IL-27 in acute graft-versus-host disease is not yet fully understood.In this study,utilizing mice with IL-27 p28 deficiency in dendritic cells(DCs),we demonstrated that IL-27 p28 deficiency resulted in impaired Treg cell function and enhanced effector T cell responses,corresponding to aggravated aGVHD in mice.In addition,using single-cell RNA sequencing,we found that loss of IL-27 p28 impaired Treg cell generation and promoted IL1R2^(+)TIGIT^(+)pathogenic CD4+T cells in the thymus at a steady state.Mechanistically,IL-27 p28 deficiency promoted STAT1 phosphorylation and Th1 cell responses,leading to the inhibition of Treg cell differentiation and function.Finally,patients with high levels of IL-27 p28 in serum showed a substantially decreased occurrence of grade II-IV aGVHD and more favorable overall survival than those with low levels of IL-27 p28.Thus,our results suggest a protective role of DC-derived IL-27 p28 in the pathogenesis of aGVHD through modulation of the Treg/Teff cell balance during thymic development.IL-27 p28 may be a valuable marker for predicting aGVHD development after transplantation in humans.展开更多
基金We thank Ziling Zhu of Soochow University for irradiation of the mice. This work has been supported by grants from the National Natural Science Foundation of China (81273268, 81471586, 81273259, 81471589 and 81500145)the Natural Science Foundation of Jiangsu Province (BK20150352)+1 种基金project funding from Suzhou city (SWG0904)and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘The role of IL-17 and IL-17-producing CD4^(+) T cells in acute graft-versus-host disease(GVHD)has been controversial in recent mouse and human studies.We carried out studies in a murine acute GVHD model of fully major histocompatibility complex-mismatched myeloablative bone marrow transplantation.We showed that donor wild-type CD4^(+) T cells exacerbated acute GVHD compared with IL-17−/−CD4^(+) T cells,while IL-17 reduced the severity of acute GVHD.The augmentation of acute GVHD by transferred donor IL-17-producing CD4^(+) T cells was associated with increased Th1 responses,while IL-17 decreased the percentages of Th1 cells in the GVHD target organs.Furthermore,IL-17 reduced the infiltration of macrophages into the GVHD tissues.In vitro study showed that IL-17 could downregulate Th1 responses,possibly through inhibiting IL-12 production by donor macrophages.Depletion of macrophages in vivo diminished the protective effect of IL-17.Our results demonstrated the differential roles of adoptively transferred donor IL-17-producing CD4^(+) T cells and IL-17 in the same acute GVHD model.
基金This work has been supported by the grants from the National Natural Science Foundation of China (91029703, 81072436 and 81273268), with project funding from Suzhou City (SWG0904, SZS201109), Priority Academic Program Development of Jiangsu Higher Education Institutions, Qing Lan Project of Jiangsu Province, Jiangsu Provincial Innovative Research Team and the Program for Changjiang Scholars and Innovative Research Team in University (IRT1075).
文摘FTY720, an agonist for four of the five known sphingosine- 1-phosphate (SIP) receptors, has been reported to inhibit acute graft-versus-host disease (aGVHD). Because FTY720 functions through multiple SIP receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective SIP receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an SIPl-selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an SIPl-selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.
基金This work was supported by the Projects of International Cooperation and Exchanges NSFC(82020108003)National Natural Science Foundation of China(Nos.81730003,81773361,81974001,and 81900180)+11 种基金National Science and Technology Major Project(2017ZX09304021)National Key R&D Program of China(2019YFC0840604 and 2017YFA0104502)Key R&D Program of Jiangsu Province(BE2019798)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD),Jiangsu Medical Outstanding Talents Project(JCRCA2016002)Jiangsu Provincial Key Medical Center(YXZXA2016002)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX19_1991)the Jiangsu"333"Talent Project(BRA2015497)the Jiangsu Social Development Program(BE2018651)the Jiangsu Summit Six Top Talent Person projea,Jiangsu Medical Junior Talent Person award(QNRC2016707)the Applied Basic Research Programs of Suzhou City(SYS2018027)China Postdoctoral Science Foundation(2019M661938)Jiangsu Planned Projects for Postdoctoral Research Funds(2019K098).
文摘Dear Editor,Acute graft-versus-host disease(aGVHD)is the leading cause of transplantation-related mortality,and limits therapeutic benefits of allogeneic bone marrow transplantation(allo-BMT).New insight is needed into the development of aGVHD.Most nutritional metabolites contribute to host health and immune homeostasis.
基金supported by the National Natural Science Foundation of China(No.81730003,81700173,81974001,82170222,and 81900180)National Science and Technology Major Project(2017ZX09304021)+9 种基金National Key R&D Program of China(2019YFC0840604 and 2017YFA0104502)Key R&D Program of Jiangsu Province(BE2019798)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD),Jiangsu Medical Outstanding Talents Project(JCRCA2016002)Jiangsu Provincial Key Medical Center(YXZXA2016002)the Jiangsu“333”Talent Project(BRA2015497)the Jiangsu Social Development Program(BE2018651)the Jiangsu Summit Six Top Talent Person project,Jiangsu Medical Junior Talent Person award(QNRC2016707)Natural Science Foundation of Jiangsu Province(BK20220246),Suzhou Science and Technology Program Project(SLT201911)the Natural Science Foundation of Jiangsu Higher Education Institutions of China(20KJD320001)Natural Science Basic Research Program of Shaanxi(2022JQ-800).
文摘Interleukin 27(IL-27),a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28,is a pleiotropic cytokine with both pro-and anti-inflammatory properties.However,the precise role of IL-27 in acute graft-versus-host disease is not yet fully understood.In this study,utilizing mice with IL-27 p28 deficiency in dendritic cells(DCs),we demonstrated that IL-27 p28 deficiency resulted in impaired Treg cell function and enhanced effector T cell responses,corresponding to aggravated aGVHD in mice.In addition,using single-cell RNA sequencing,we found that loss of IL-27 p28 impaired Treg cell generation and promoted IL1R2^(+)TIGIT^(+)pathogenic CD4+T cells in the thymus at a steady state.Mechanistically,IL-27 p28 deficiency promoted STAT1 phosphorylation and Th1 cell responses,leading to the inhibition of Treg cell differentiation and function.Finally,patients with high levels of IL-27 p28 in serum showed a substantially decreased occurrence of grade II-IV aGVHD and more favorable overall survival than those with low levels of IL-27 p28.Thus,our results suggest a protective role of DC-derived IL-27 p28 in the pathogenesis of aGVHD through modulation of the Treg/Teff cell balance during thymic development.IL-27 p28 may be a valuable marker for predicting aGVHD development after transplantation in humans.